title: Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease.
abstract: Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. gal@uke.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Isabella
authors.initials: I
authors.lastname: Rau
authors.forename: Leila
authors.initials: L
authors.lastname: El Matri
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Kreienkamp
authors.forename: Susanne
authors.initials: S
authors.lastname: Fehr
authors.forename: Karim
authors.initials: K
authors.lastname: Baklouti
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Chouchane
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Monika
authors.initials: M
authors.lastname: Rehbein
authors.forename: Josefine
authors.initials: J
authors.lastname: Fuchs
authors.forename: Hans C
authors.initials: HC
authors.lastname: Fledelius
authors.forename: Kaj
authors.initials: K
authors.lastname: Vilhelmsen
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.forename: Elsebet
authors.initials: E
authors.lastname: Ostergaard
authors.forename: Debra A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Thomas
authors.initials: T
authors.lastname: Rosenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005123:Eye / Q000201:enzymology / Q000473:pathology; D005190:Family; D015971:Gene Expression Regulation, Enzymologic; D005808:Genes, Recessive / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008850:Microphthalmos / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D057057:Serine Proteases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C114880:trypsin-like serine protease; C558176:PRSS56 protein, human; D057057:Serine Proteases; D012697:Serine Endopeptidases